Mammalian aging is a multi-organ process characterized by loss of tissue regenerative potential. It has been increasingly recognized that tissue-specific stem cells may underlie the aging process, but the degree that they are involved may vary substantially between different tissues and should be carefully evaluated on a tissue-by-tissue basis. (Rossi, D. J. et al., Cell 132, 681-696 (2008)) Hematopoietic stem cells (HSCs) are the best characterized adult tissue stem cells. HSC aging contributes to several pathophysiological conditions in the elderly including the onset of anemia, (Beghe, C. et al., Am J Med 116 Suppl 7A, 3S-10S (2004).) the decline of immune competence, (Linton, P. J. & Dorshkind, Nat Immunol 5, 133-139 (2004)) and the increased incidence of hematological malignancies particularly myeloid leukemia. (Lichtman, M. A. & Rowe, J. M., Semin Oncol 31, 185-197 (2004)) Aging HSCs exhibit increased cell cycle entry and expansion of the HSC compartment along with a skewed differentiation program favoring myeloid lineage. (Morrison, S. J. et al., Nat Med 2, 1011-1016 (1996); Pang, W. W. et al., Proc Natl Acad Sci USA 108, 20012-20017 (2011)) Aging HSCs display an intrinsic transcriptome change, (Rossi, D. J. et al., Proc Natl Acad Sci USA 102, 9194-9199 (2005)) and the skewing of lineage potential is attributed to clonal expansion of myeloid-biased HSCs during aging. (Challen, G. A. et al., Cell stem cell 6, 265-278 (2010); Beerman, I. et al., Proc Natl Acad Sci USA 107, 5465-5470 (2010); Cho, R. H. et al., Blood 111, 5553-5561 (2008)) It has been postulated that aging is a consequence of life long exposure to free radical or oxidative stress, (Harman, D., J Gerontol 11, 298-300 (1956)) which causes cellular damage. Spontaneous DNA damage is indeed accumulated in aged HSCs and genome maintenance machineries including non-homologous end joining (NHEJ) repair are required for maintaining HSC functions during aging. (Rossi, D. J. et al., Nature 447, 725-729 (2007); Nijnik, A. et al., Nature 447, 686-690 (2007)) But, how self-renewal and lineage determination of HSCs during aging are molecularly controlled is poorly understood.
Sirtuins are a family of mammalian lysine modifying enzymes involved in regulating metabolism, aging and cancer. (Houtkooper, R. H. et al., Nat Rev Mol Cell Bio 13, 225-238 (2012); Saunders, L. R. et al., Oncogene 26, 5489-5504 (2007)) Sirtuins are homologues of yeast silent information regulator 2 (Sir2) that encodes a NAD-dependent histone deacetylase. (Imai, S. et al., Nature 403, 795-800 (2000)) Initial studies in lower organisms showed that increased Sir2 gene dosage is sufficient to extend lifespan, (Kaeberlein, M. et al., Genes Dev 13, 2570-2580 (1999); Tissenbaum, H. A. & Guarente, L., Nature 410, 227-230 (2001)) and that Sir2 is the major effector for caloric restriction (CR) or CR mimetics for increasing longevity. (Howitz, K. T. et al., Nature 425, 191-196 (2003); Wood, J. G. et al., Nature 430, 686-689 (2004)) Sirtuin 1 (SIRT1) shares the highest homology with yeast Sir2 and is the most extensively studied mammalian sirtuin. SIRT 1 is a stress response gene encoding a multi-functional protein deacetylase that regulates epigenetic gene silencing, DNA damage repair, cell survival under stress, and energy homeostasis. (Houtkooper, R. H. et al., Nat Rev Mol Cell Bio 13, 225-238 (2012); Saunders, L. R. et al., Oncogene 26, 5489-5504 (2007)) Over-expression of SIRT1 is shown to improve mouse aging but fails to increase lifespan, and noticeably, does not reduce age-dependent development of lymphoma and histiocytic lymphoma. (Herranz, D. et al., Nat Commun 1, 3 (2010))
There is a need in the art for methods and compostions of treating hematological diseases. Disclosed herein are methods of using SIRT1 inhibitors, which are surprisingly effective to prevent or treat age-related, cancerous or non-cancerous hematological disease, thereby curing these and other needs in the art.